The road to effective cancer vaccines has been long and difficult.
Although initial attempts to use a vaccine to treat cancer date back to the 1910s, the first effective therapeutic vaccine would not emerge until about a century later, when Sipuleucel-T was used to treat prostate cancer in 2010. While the FDA-approved prostate cancer vaccine generated much excitement, its success has proven difficult to replicate. T-VEC, used to treat metastatic melanoma, is the only other cancer therapeutic vaccine approved by the FDA. While there are some preventative vaccines against viruses associated with cancer (vaccines against HPV and hepatitis B, for example), vaccines that prevent cancer directly have proven elusive.
However, as the speakers and panelists at the Koch Institute for Integrative Cancer Research’s annual symposium on June 23 demonstrated, cancer vaccine research is at a pivotal moment.
“We’ve all learned over the past several years due to the Covid-19 pandemic, when vaccine therapies and vaccine development were put to the ultimate test, what is really possible,” said Koch Institute Director Matthew Vander Heiden in his opening remarks. With more than a dozen ongoing clinical trials of mRNA cancer vaccines, Vander Heiden believes that we may be “close to a new revolution of cancer vaccines.”
A panel discussion laid out the obstacles that face cancer vaccine researchers, especially in terms of therapeutic vaccines. As noted by panel moderator and Koch Institute Associate Director Darrell Irvine, a 2004 analysis showed that only 2.6 percent of patients saw sustained reduction in tumor size after receiving a cancer vaccine. Ideally, therapeutic vaccines train the immune system to recognize and destroy cancer cells by targeting tumor associated antigens — molecules present only on the surface of cancer cells or more abundant on cancer cells than on normal cells. However, tumor biology is complex, with a tumor microenvironment that suppresses immune activity and a vast molecular diversity that makes the identification of effective target antigens challenging.
However, the tools available to cancer and immunology researchers have become far more sophisticated in the past two decades, as Catherine J. Wu, a professor of medicine and chief of the Division of Stem Cell Transplantation and Cellular Therapies at the Dana-Farber Cancer Institute, explained. Recent technological advancements such as mass spectrometry, “omics” platforms for analyzing single cell expression of genes and proteins, neoantigen prediction, and computational biology and machine learning — as well as improvements to mouse and other cancer models — have provided essential insights into the biology of cancer and the immune response.
Several of the symposium’s presentations demonstrated the power of these next-generation tools:
Keynote speaker Frederica Sallusto, professor of medical immunology at ETH Zürich, shared some of her laboratory’s progress in creating sensitive, high-throughput platforms integrating various omics technologies, with the goal of understanding human T and B cell response to cancer and infection, and the behavior of immune cells in autoimmune disorders.
Michal Bassani-Sternberg, an assistant professor at the Lausanne University Hospital in Switzerland, presented her work using omics platforms and machine learning to characterize the features of tumors and their microenvironments to improve vaccine strategies and antigen selection for the differing genetic landscapes of lung tumors in smokers and nonsmokers.
Tyler Jacks, the David H. Koch Professor of Biology at MIT, described work in his laboratory to develop mouse models that help researchers define cancer-specific antigens and study tumor immune interactions.
Malte Roerden, a postdoc in the Koch Institute laboratory of Stefani Spranger, showed how differences in antigen expression among cancer cells and interactions between antigens lead to starkly different outcomes among patients treated with immune checkpoint blockade therapies.
Charles Swanton, a principal group leader at the Francis Crick Institute, London, U.K., shared his findings on how air pollution causes non-small lung cancer in never-smokers, although, unlike smoking, air pollution does not directly cause oncogenic mutations.
A next step forward in the development of effective cancer vaccines, according to the panel discussion, may be mRNA vaccines that are tailored to individual patients according to cancer-specific antigens presented by their tumors. Because development of mRNA vaccines is much quicker than that of traditional recombinant protein-based vaccines, they make it more feasible to develop personalized treatments.
The emergence of mRNA vaccine technology has been decades in the making, according to panelist Robert Langer, the David H. Koch Institute Professor, due in part to obstacles in developing lipid nanoparticles that could deliver the genetic payload to cells. Although he developed some of the earliest functional nanoparticles in the 1970s, “people didn’t think it was possible, even after we did it.” Nevertheless, Langer and many other researchers began to solve problems in the delivery of biological molecules such as DNA, RNA, and proteins, such as preventing the aggregation of nanoparticles, ensuring cellular uptake and reducing toxicity.
Kyle Holen, head of Development, Therapeutics, and Oncology at Moderna, believes that while the process of developing personalized mRNA vaccines is “not for the faint of heart, it offers a wealth of opportunities.” The use of algorithms as part of the manufacturing process presents unique regulatory challenges, while logistical difficulties, such as shipping materials and obtaining specimens from pathology labs, impact the speed of vaccine production.
Despite these challenges, personalized mRNA vaccines are delivering promising results in clinical trials. Holen highlighted the results from ongoing clinical trials of two personalized mRNA cancer vaccines that were tailored to the antigens presented by individual patient tumors. The first, developed by BioNTech in partnership with Genentech for treating pancreatic cancer, was given alongside checkpoint blockade therapy after surgery, and resulted in almost no recurrence of tumors after 18 months of follow-up for patients who responded to the vaccine. The second vaccine, developed by Moderna in partnership with Merck, showed a 44 percent decrease in the recurrences of melanoma and a 65 percent decrease in distant metastases.
mRNA vaccines were not alone in showing signs of promise at the symposium. Peter DeMuth, chief scientific officer at Elicio Therapeutics, shared positive results from an ongoing clinical trial of a technology developed in the Irvine laboratory that delivers cancer vaccines to lymph nodes for more potent activation of antitumor immunity. Designed to target cancers with mutation to KRAS, a mutation shared by many solid tumors, the vaccine was given to patients with pancreatic and colorectal cancers. Seventy-seven percent of patients experienced a reduction in biomarkers that show the persistence of tumors, and 32 percent cleared those biomarkers altogether.
Olivera Finn, distinguished professor of immunology and surgery at the University of Pittsburgh School of Medicine, shared her progress in developing a preventative cancer vaccine. Finn observed that some healthy people who have never had cancer still show immune responses to cancer-associated antigens. Some immune events, such as viral and bacterial infections or bone fractures, prime the immune system to recognize cancer cells. During these events, the body’s cells may express antigens — for instance, to signal damage that needs to be cleared by the immune system — that cancer cells may also express in abundance. Her findings led to the development of a preventative cancer vaccine, which in clinical trial showed a significantly lower rate of recurrence of advanced adenomas, the immediate precursor to colon cancer.